Non-rapid eye movement sleep and wake neurophysiology in schizophrenia

Abstract

Motivated by the potential of objective neurophysiological markers to index thalamocortical function in patients with severe psychiatric illnesses, we comprehensively characterized key non-rapid eye movement (NREM) sleep parameters across multiple domains, their interdependencies, and their relationship to waking event-related potentials and symptom severity. In 72 schizophrenia (SCZ) patients and 58 controls, we confirmed a marked reduction in sleep spindle density in SCZ and extended these findings to show that fast and slow spindle properties were largely uncorrelated. We also describe a novel measure of slow oscillation and spindle interaction that was attenuated in SCZ. The main sleep findings were replicated in a demographically distinct sample, and a joint model, based on multiple NREM components, statistically predicted disease status in the replication cohort. Although also altered in patients, auditory event-related potentials elicited during wake were unrelated to NREM metrics. Consistent with a growing literature implicating thalamocortical dysfunction in SCZ, our characterization identifies independent NREM and wake EEG biomarkers that may index distinct aspects of SCZ pathophysiology and point to multiple neural mechanisms underlying disease heterogeneity. This study lays the groundwork for evaluating these neurophysiological markers, individually or in combination, to guide efforts at treatment and prevention as well as identifying individuals most likely to benefit from specific interventions.

Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients

“…Sleep spindles (12-15 Hz) are another EEG feature typical of NREM sleep, generated by neurons across the cortex, thalamus, and thalamic reticular nucleus (TRN) [26]. Although rather heterogenous, patients with schizophrenia or bipolar disorder have on average a lower sleep spindle density relative to healthy comparison subjects [27, 35]. Despite sharing several other key features, the EEG phenotypes of Grin2a and Akap11 mutants showed opposite and striking changes in sleep spindles.…”

“…The present work provides an in-depth characterization of EEG phenotypes across different behavioral states (sleep, wake, auditory stimulation) and ages (3 and 6 months) in Grin2a and Akap11 and heterozygous (Het) and homozygous knockout (KO) mice, as compared with their wild-type littermates (WT). We found that Grin2a and Akap11 mutant mice possess a number of EEG features shared with human schizophrenia and bipolar disorder patients, including elevated gamma oscillations at rest [22, 23], attenuated auditory steady-state responses (ASSR) at 40-50 Hz [24, 25], and changes in sleep spindle density [26, 27]. These mouse EEG phenotypes reveal systems-level abnormalities caused by (even heterozygous) mutations in Grin2a and Akap11 , and provide further justification, beyond their genetic validity, that these mouse mutants can serve as useful animal models of schizophrenia/bipolar disorder.…”

Transient oscillation dynamics during sleep provide a robust basis for electroencephalographic phenotyping and biomarker identification

“…Figure 8 shows a comparison between the TF-peak density SO histograms in HC and medicated participants with SZ for C3 on night 2. Significantly reduced spindle activity has been observed in chronic medicated patients with SZ, as well as in antipsychotic naïve patients with early course SZ and their first-degree nonpsychotic relatives—even when exhibiting normal sleep quality and architecture [ 11 , 16 , 80 , 81 ]. Thus, reduced activity in traditionally detected spindles has been proven important as a SZ biomarker and also a target for intervention to improve sleep-dependent memory consolidation [ 10–15 , 74 , 82 ].…”

Reducing brain kynurenic acid synthesis precludes kynurenine-induced sleep disturbances

“…Reduced spindle density is a hallmark endophenotype of sleep dysfunction in patients with psychotic disorders and may serve as a predictor for cognitive and executive dysfunction. [68][69][70][71][72][73] In addition, several preclinical models relevant to the study of neuropsychiatric illnesses have also noted reduced sleep spindle density in rodents. 43,74,75 Of note is that sleep spindle spectra power during KYNA elevation was initially reduced in the lower sigma range and, perhaps as a consequence of an increased cortical drive to ameliorate reduced spindle density, the power spectra was then elevated in the upper sigma range in male subjects.…”